ProNGF/p75NTR Axis Drives Fiber Type Specification by Inducing the Fast-Glycolytic Phenotype in Mouse Skeletal Muscle Cells

Abstract

Despite its undisputable role in the homeostatic regulation of the nervous system, the nerve growth factor (NGF) also governs the relevant cellular processes in other tissues and organs. In this study, we aimed at assessing the expression and the putative involvement of NGF signaling in skeletal muscle physiology. To reach this objective, we employed satellite cell-derived myoblasts as an in vitro culture model. In vivo experiments were performed on Tibialis anterior from wild-type mice and an mdx mouse model of Duchenne muscular dystrophy. Targets of interest were mainly assessed by means of morphological, Western blot and qRT-PCR analysis. The results show that proNGF is involved in myogenic differentiation. Importantly, the proNGF/p75NTR pathway orchestrates a slow-to-fast fiber type transition by counteracting the expression of slow myosin heavy chain and that of oxidative markers. Concurrently, proNGF/p75NTR activation facilitates the induction of fast myosin heavy chain and of fast/glycolytic markers. Furthermore, we also provided evidence that the oxidative metabolism is impaired in mdx mice, and that these alterations are paralleled by a prominent buildup of proNGF and p75NTR. These findings underline that the proNGF/p75NTR pathway may play a crucial role in fiber type determination and suggest its prospective modulation as an innovative therapeutic approach to counteract muscle disorders.

Neurotrophins as Key Regulators of Cell Metabolism: Implications for Cholesterol Homeostasis

“…NTs are a small family of growth factors significantly involved in the regulation, development and function of the nervous system [ 6 , 7 ]. In 1951, Nobel laureate Rita Levi-Montalcini discovered the nerve growth factor (NGF), a neutrophin able to enhance the growth of sensory and sympathetic neurons [ 8 , 9 ].…”

“…Pro-NTs are proteolytically cleaved by proteases to obtain mature neurotrophins with a molecular weight of approximately 13–14 kDa [ 14 , 15 ]. The production of mature NTs is cell-tissue dependent and their expression pattern may vary according to cell context and physiopathological condition [ 7 ]. For instance, proprotein convertase subtilisin/kexin 3 (PCSK9, or furin) is expressed in most mammalian cells, while proprotein convertase subtilisin/kexin 1 (PCSK1, or NEC1) and proprotein convertase subtilisin/kexin 2 (PCSK2, or NEC2) preferentially show neuronal expression.…”

“…These enzymes expression is subjected to elegant physiological regulations, and a considerable amount of pro-NTs can be directly secreted in the extracellular milieu in specific contexts. Once secreted, mature NTs influence a variety of aspects related to the development and the functioning of the nervous system, such as neurite extension, axonal growth and neuronal differentiation, myelination, synaptic plasticity, survival and apoptosis [ 6 , 7 , 16 ]. In the extracellular space, pro-NTs may undergo proteolytic processing by the activity of plasmin and/or matrix metalloproteases (for extensive review, please see ref.…”

“…[ 17 , 18 , 19 ]). Interestingly, it is now well-established that, independently from their mature forms, pro-NTs exert biological activity and may display different, even opposite, effects if compared to their mature counterparts [ 6 , 7 ].…”

“…p75NTR has also been reported to interact with Necdin. This MAGE-related protein together with E2F1, E2F4 and p53, represents a key regulator of the cell cycle, differentiation and survival in several tissues [ 7 , 51 , 52 ]. p75NTR activation is also implicated in the regulation of PKA signaling.…”